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Lung Adenocarcinoma in Non‐Smokers May Be Unique Disease

ISTANBUL, TURKEY—Adenocarcinoma has become the most common histological type of lung cancer, and with that the proportion of women and never-smokers suffering from lung cancer is on the rise. Already, genomic and epigenetic data suggest that lung adenocarcinoma in people who have never smoked may be a different disease than that which affects smokers. Now, researchers from Institute Gustave Roussy in Villejuif, France, have found that the protein signaling pathways also differ between tumors from the two populations.

“Our results indicated that two members of a specific family of proteins, the MAP kinase family, were significantly overexpressed in non-smokers relative to smokers,” said Giannis Mountzios, MD, a resident in the Department of Translational Research at the institute, who presented the work here at the European Society for Medical Oncology Congress.

“These data support the existing epidemiological and genetic evidence that lung adenocarcinoma in never smokers may constitute a distinct biological entity among lung cancer patients.”

Although the data do not have immediate application in the clinic, the better that scientists understand the underlying molecular cause of disease, the more likely it will be that appropriate targeted therapies can be developed. Additionally, such information will be useful in helping select appropriate patients for trials testing targeted therapies that already exist.

ESMO Late-Breaking Abstract LBA7

In fact, looking at it another way, Jean-Yves Douillard, MD, PhD, Professor and Head of the Department of Medical Oncology at the Centre René Gauducheau in Saint Herblain, France, said the new data are consistent with what has already been seen in trials with epidermal growth factor receptor inhibitors in which never smokers are more likely to respond than patients with a smoking history.

That supports the idea that there are multiple disease mechanisms at play in lung cancer, he said.

In the current study, Dr. Mountzios and colleagues used high-throughput tissue arrays and immunohistochemistry to analyze samples from 188 patients with adenocarcinoma who were treated at the Institute Gustave Roussy between 1995 and 2002. Of those, 45 were never smokers and 143 were former or current smokers.

“Our analysis confirmed already existing data in the literature that never smokers with lung adenocarcinoma are more likely to be women than men, that they tend to have an older age at diagnosis than smokers, and that the subtype of lung adenocarcinoma with bronchoalveolar features tends to be more frequent in never smokers compared with smokers with lung adenocarcinoma,” Dr. Mountzios said.

More to the point, however, the team found that two members of the MAP kinase signaling pathway, p38 and JNK, were significantly overexpressed in nonsmokers compared with smokers in a univariate analysis.

A multivariate analysis demonstrated that p38 was more than 10-fold more abundant in the tumors of never smokers than in tumors from patients with a smoking history, and that that difference was highly significant. The JNK overexpression did not remain statistically significant in the multivariate analysis.

Using a correlation analysis, Dr. Mountzios's group saw that expression of p38 and JNK coincided with increases in STAT3 and phosphorylated AKT. All of these proteins are known to drive cell proliferation and suggest that this signaling pathway is a key factor in adenocarcinoma in non-smokers.

None of the molecular markers had any independent prognostic value, Dr. Mountzios noted.

‘Very Exciting Piece of Work’

I think this is a very exciting piece of work,' said Margaret A. Tempero, MD, Associate Director for Clinical Sciences at the University of California Comprehensive Cancer Center in San Francisco, a former President of ASCO, who chaired the late-breaking abstracts session in which Dr. Mountzios presented the work.

“But I am actually more interested in the application to risk stratification than to therapy, because one wonders if whatever leads to a different molecular profile in never smokers might also be an underlying abnormality that could be identified in germline DNA and perhaps be used to risk-stratify individuals.”

Dr. Mountzios acknowledged the possibility and said that with the success of this first study, the team is making plans for additional ones, including starting to look for specific gene patterns that predispose an individual to this type of disease.

A new ultrasound technique called elasticity imaging has been shown to allow radiologists to accurately distinguish benign from malignant breast lesions, according to a study reported at the Radiological Society of North America Annual Meeting.

The researchers used the technique to correctly identify both cancerous and harmless lesions in nearly all of the cases studied.

“In our work, elasticity imaging has been found to have high specificity,” Richard G. Barr, MD, PhD, Professor of Radiology at Northeastern Ohio Universities College of Medicine and a radiologist at Southwoods X-Ray and MRI in Youngstown, OH, said in a news release.

“If our results can be reproduced in a large, multicenter trial, this technique could significantly reduce the number of breast biopsies required.”

Elasticity imaging is a modification of a routine ultrasound exam, he explained. It is like a manual self-exam but much more sensitive. The noninvasive technique works by gauging how much tissue moves when pushed, and it can detect how soft or stiff an object is.

“There are no needles,” Dr. Barr noted. “The patient does not notice any difference from a standard ultrasound.”

Dr. Barr used a real-time, free-hand, elasticity imaging technique in correlation with a routine ultrasound exam to study 166 lesions identified and scheduled for biopsy in 99 patients.

Lesions were measured for the largest length on both the standard ultrasound image and the elasticity image. Lesions where the elasticity image was smaller than the standard image were characterized as benign, and lesions where the elasticity image was larger were characterized as malignant.

Ultrasound-guided biopsies were performed on 80 patients with 123 lesions. Biopsy showed that elasticity imaging correctly identified all 17 malignant lesions and 105 of 106 benign lesions, for a sensitivity of 100% and a specificity of 99%.

He said he anticipates that elasticity imaging will also help in detecting cancers, although that was not evaluated in this study.

He and his colleagues are planning to expand their research in an international, multicenter trial expected to start in January, he said.

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